Water soluble film for oral administration with instant wettability

ABSTRACT

A composition containing therapeutic agents and/or breath freshening agents for use in the oral cavity is disclosed. The carrier comprises water-soluble polymers in combination with certain ingredients and provides a therapeutic and/or cosmetic effect. The film is coated and dried utilizing existing coating technology and exhibits instant wettability followed by rapid dissolution/disintegration upon administration in the oral cavity.

This is a continuation of Ser. No. 08/904,607, filed Aug. 1, 1997, nowU.S. Pat. No. 5,948,430.

BACKGROUND OF THE INVENTION

A composition containing therapeutic agents and/or breath fresheningagents for use in the oral cavity is disclosed. The carrier compriseswater-soluble polymers in combination with certain ingredients andprovides a therapeutic and/or cosmetic effect. The film is coated anddried utilizing existing coating technology and exhibits instantwettability followed by rapid dissolution/disintegration uponadministration in the oral cavity.

Mucoadhesive dosage forms for application to the oral cavity which aredesigned to deliver therapeutic and/or cosmetic agents to the oralmucosa are known in the art. U.S. Pat. No. 5,047,244 described amucoadhesive carrier allowing the controlled release of a therapeuticagent via the mucosal tissue comprising an anhydrous but hydratablepolymer matrix and amorphous fumed silica. An optional water-insolublefilm can be added to provide a non-adhering surface. In WO 91/06270, thesame authors disclose a trilaminate film suitable for prolonged deliveryof an active ingredient in the oral cavity.

In a similar way, U.S. Pat. No. 4,876,092 disclosed a sheet-shapedadhesive preparation comprising an adhesive layer containing certainwater-soluble and water-insoluble polymers and a water-insoluble carrierwhich can adhere to the oral mucosa thereby releasing an active agent tothe oral cavity. All the devices so far cited are not completely watersoluble and will stay in the oral cavity even after the therapeutic goalhas been achieved leaving the patient with a certain discomfort in themouth resulting mainly from the support layer which leaves an insolubleresidue in the mouth.

A number of attempts have been made to reduce the adverse feeling in theoral cavity caused by the rigidity and inflexibility of the supportlayer by introducing soft film supports. EP 0 200 508 B1 and EP 0 381194 B1 disclose the use of polyethylene films, polyvinyl acetate,ethylene-vinyl acetate copolymers, metal foils, laminates of cloth orpaper and a plastic film, and similar materials as soft film supports,whereby synthetic resin like polyethylene, vinyl acetate homopolymers,and ethylene-vinyl acetate are the preferred materials. In a similarway, CA 1 263 312 discloses the use of polyolefines such aspolyethylene, polypropylene, polyesters, PVC, and non-woven fabrics assoft support materials.

However, these devices still leave the patient with a considerableamount of residue from the water-insoluble support film thereby stillcausing a feeling of discomfort. The obvious solution to overcome thisproblem was to develop mucoadhesive films which completely disintegrate,or even completely dissolve in the saliva. Fuchs and Hilmann (DE 24 49865.5) prepared homogeneous, water-soluble films intended for buccaladministration of hormones. They proposed the use of water-solublecellulose-derivatives, like hydroxyethyl cellulose, hydroxypropylcellulose, or methyl hydroxypropyl cellulose, as film forming agents.

Both DE 36 30 603 and EP 0 219 762 disclose the use of swellablepolymers such as gelatine or corn starch as film forming agents, whichupon application to the oral cavity slowly disintegrate, therebyreleasing an active ingredient incorporated in the film. The samepolymers can also be used to prepare films which are intended for dentalcleansing, as described in EP 0 452 446 B1.

These preparations still create an adverse feeling in the mouth which ismainly caused by their initial rigidity and delayed softening. Thus,there has still been a demand for a composition for use in the oralcavity which meets the requirement of providing a pleasant feeling inthe mouth. The present invention discloses methods and compositions thatare capable of avoiding an adverse feeling by providing the film whichis intended for application to the oral mucosa with instant wettability,while achieving adequate tensile strength in the free film to allow foreasy coating, converting, and packaging of a consumer-friendly product.

The present invention contemplates a rapidly dissolving film which canbe adhered to the oral cavity thereby releasing a pharmaceutically orcosmetically active agent, said film comprising water-soluble polymers,one or more polyalcohols, and one or more pharmaceutically orcosmetically active ingredients. Optionally, the formulation may containa combination of certain plasticizers or surfactants, colorants,sweetening agents, flavors, flavor enhancers, or other excipientscommonly used to modify the taste of formulations intended forapplication to the oral cavity. The resulting film is characterized byan instant wettability which causes the film to soften immediately afterapplication to the mucosal tissue thus preventing the patient fromexperiencing any prolonged adverse feeling in the mouth, and a tensilestrength suitable for normal coating, cutting, slitting, and packagingoperations.

The mucoadhesive film of the present invention contains as essentialcomponents a water-soluble polymer or a combination of water-solublepolymers, one or more plasticizers or surfactants, one or morepolyalcohols, and a pharmaceutically or cosmetically active ingredient.

The polymers used for the mucoadhesive film include polymers which arehydrophilic and/or water-dispersible. Preferred polymers arewater-soluble cellulose-derivatives. Hydroxypropylmethyl cellulose,hydroxyethyl cellulose, or hydroxypropyl cellulose, either alone, ormixtures thereof, are particularly preferred. Other optional polymers,without limiting the invention, include polyvinyl pyrrolidone,carboxymethyl cellulose, polyvinyl alcohol, sodium alginate,polyethylene glycol, natural gums like xanthane gum, tragacantha, guargum, acacia gum, arabic gum, water-dispersible polyacrylates likepolyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers.The concentration of the water-soluble polymer in the final film canvery between 20 and 75% (w/w), preferably between 50 and 75% (w/w).

The surfactants used for the mucoadhesive film may be one or morenonionic surfactants. When a combination of surfactants is used, thefirst component may be a polyoxyethylene sorbitan fatty acid ester or aα-hydro-ω-hydroxypoly (oxyethylene)poly(oxypropylene)poly(oxyethylene)block copolymer, while the second component may be a polyoxyethylenealkyl ether or a polyoxyethylene castor oil derivative. Preferably, theHLB value of the polyoxyethylene sorbitan fatty acid ester should bebetween 10 and 20, whereby a range of 13 to 17 particularly preferred.The α-hydro-ω-hydroxypoly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymer should contain at least 35oxypropylene-units, preferably not less than 50 oxypropylene-units.

The polyoxyethylene alkyl ether should have an HLB value between 10 and20, whereby an HLB value of not less than 15 is preferred. Thepolyoxyethylene castor oil derivative has to have an HLB value of 14-16.

In order to achieve the desired instant wettability, the ratio betweenthe first and second component of the binary surfactant mixture shouldbe kept within 1:10 and 1:1, more preferably between 1:5 and 1:3.

The total concentration of surfactants in the final film depends on theproperties of the other ingredients, but usually has to stay between 0.1and 5% (w/w).

The polyalcohol is used to achieve the desired level of softness of thefilm. Examples of a polyalcohols include glycerol, polyethylene glycol,propylene glycol, glycerol monoesters with fatty acids or otherpharmaceutically used polyalcohols. The concentration of the polyalcoholin the dry film usually ranges between 0.1 and 5% (w/w).

The film is well suited for the delivery of a wide range ofpharmaceutically active ingredients via the mucous membranes of apatient, particularly the buccal mucosa. Therapeutic agents whichexhibit absorption problems due to solubility limitations, degradationin the gastro-intestinal tract, or extensive metabolism, areparticularly well suited. Without limiting the invention, examples ofthe therapeutic agents include hypnotics, sedatives, antiepileptics,awakening agents, psychoneurotropic agents, neuromuscular blockingagents, antispasmodic agents, antihistaminics, antiallergics,cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors,antitussive expectorants, thyroid hormones, sexual hormones,antidiabetics, antitumor agents, antibiotics and chemotherapeutics, andnarcotics.

The amount of drug to be incorporated into the film depends on the kindof drug and is usually between 0.01 and 20% (w/w), but it can be higherif necessary to achieve the desired effect.

Cosmetically active agents may include breath freshening compounds likementhol, other flavors or fragrances commonly used for oral hygiene,and/or actives used for dental and/or oral cleansing like quarternaryammonium bases. The effect of flavors may be enhanced using flavorenhancers like tartaric acid, citric acid, vanillin, or the like.Colorants which may optionally be mixed in the film must be safe interms of toxicity and should be accepted by the Food And DrugAdministration for use in cosmetics.

The mucoadhesive film according to the present invention can be preparedas follows: The polyalcohol, surfactants, plasticizers, and possibleother ingredients except the water-soluble or water-dispersiblepolymer(s) are dissolved in a sufficient amount of a solvent which iscompatible with them. Examples of compatible solvents include water,alcohols or mixtures thereof. After a clear solution has been formed,the water-dispersible polymer or mixture of water-dispersible polymersis slowly added with stirring, and heat if necessary, until a clear andhomogeneous solution has been formed, followed by the addition of activeingredients and flavors. The solution is coated onto a suitable carriermaterial and dried to form a film. The carrier material must have asurface tension which allows the polymer solution to spread evenlyacross the intended coating width without soaking in to form adestructive bond between the two. Examples of suitable materials includenon-siliconized polyethylene terephthalate film, non-siliconized kraftpaper, polyethylene-impregnated kraft paper, or non-siliconizedpolyethylene film.

The coating of the solution onto the carrier material can be performedusing any conventional coating equipment. A more preferred coatingtechnique would involve a knife-over-roll coating head.

The thickness of the resulting film depends on the concentration ofsolids in the coating solution and on the gap of the coating head andcan vary between 5 and 200 μm. Drying of the film is carried out in ahigh-temperature air-bath using a drying oven, drying tunnel, vacuumdrier, or any other suitable drying equipment, which does not adverselyaffect the active ingredient(s) or flavor of the film. In order toreliably avoid an adverse feeling in the mouth, a dry film thickness of70 μm should not be exceeded. For better ease of use, the dry film canbe cut into pieces of suitable size and shape and packed into a suitablecontainer.

The invention will now be explained more specifically with reference tothe following examples, which are given for illustration of thisinvention and are not intended to be limiting thereof.

EXAMPLE 1

15 g of sorbitol, 6 g of glycerol, 0.5 g of polysorbate 80 (Tween 80), 2g of Brij 35, 25 g of lemon mint flavor, 3 g of aspartame, 15 g of1-menthol, and 3 g of citric acid are stirred at 60° C. in a mixture of250 g water and 250 g ethanol until a clear solution has been formed. Tothe solution, 30 g of hydroxypropylmethyl cellulose are added slowlyunder stirring until a clear and homogeneous solution has been formed.The resulting solution is allowed to cool to room temperature and coatedonto a suitable carrier material, for example non-siliconized,polyethylene-coated kraft paper using conventional coating/dryingequipment. Coating gap and web speed have to be adjustable to achieve adry film thickness between 20 and 50 μm. The drying temperature dependson the length of the drying oven and the web speed and has to beadjusted to remove the solvents completely, or almost completely, fromthe film. The resulting film is peeled off the carrier web and cut intopieces of a shape and size suitable for the intended use.

EXAMPLE 2

3 g sorbitol, 1.5 g Kollidon 30 (supplier: BASF), 5 g glycerol, 5 gpropylene glycol, 5 g polyethylene glycol, 4 g polysorbate 80 (Tween80), 8 g Brij 35, 12 g peppermint flavor, and 0.8 g aspartame aredissolved in a mixture containing 400 g water and 400 g ethanol at 60°C. under stirring. To the clear solution, 25 g hydroxypropylmethylcellulose are added slowly under stirring. After the polymer iscompletely dissolved, the solution is cooled to room temperature andcoated onto a suitable carrier web using the coating and dryingconditions as described in the previous example. The dry film is againcut into pieces of suitable size and shape.

EXAMPLE 3

15 g sorbitol, 22.5 g glycerol, 2.5 g propylene glycol, 2.5 g Brij 35,2.5 g poloxamer 407, 3.5 g Cremophor RH 40, 9 g herb mint flavor, and0.5 g aspartame are dissolved under stirring at 60° C. in a mixturecontaining 250 g water and 250 g ethanol. To the clear solution, 75 ghydroxypropyl cellulose are added slowly under continuous stirring. Theclear solution is again coated and dried under the conditions asdescribed in EXAMPLE 1 and the dry film is cut into pieces of a shapeand size suitable for the intended use.

EXAMPLE 4

3.6 g Tween 80, 3.6 g glycerol, 39 g menthol, and 171 g Kollidon 30 aredissolved in a solution of 600 ml water and 2800 ml ethanol at ambienttemperature with stirring. 247.5 g hycroxypropylmethyl cellulose is thenadded slowly and portionwise at 50-55° C. and stirred until completelydissolved. The mixture is then allowed to cool and added in successionare 90 g lemon mint flavor followed by a solution/suspension of 27.13 gaspartame, 18 g citric acid, and 0.17 g FD&C yellow #5 in 120 ml waterwith stirring. The clear solution is coated and dried under theconditions as described in EXAMPLE and the dry film is cut into piecesof a shape and size suitable for the intended use.

EXAMPLE 5

165.4 g Kollidon 30 are dissolved in a solution of 720 ml water and 2660ml ethanol at ambient temperature with stirring. 220.5 ghydroxypropylmethyl cellulose is then added at 55-60° C. and stirredvigorously until clear and homogeneous. The mixture is then allowed tocool and added in succession are 78.75 g flavor followed by a mixture of28.88 g nicotine salicylate and 31.5 g caramel liquid in 120 ml waterwith stirring. The clear, tan-colored solution is coated an dried underthe conditions as described in EXAMPLE 1 and the dry film is cut intopieces of a shape and size suitable for the intended use so as todeliver a nicotine dose between 1-2 mg per piece.

What is claimed is:
 1. A composition applicable to the oral cavitycomprising at least one water-soluble polymer, at least one polyalcohol,and at least one cosmetically or pharmaceutically active ingredient,wherein the composition has mucoadhesive properties.
 2. The compositionaccording to claim 1, wherein the cosmetically active ingredient isselected from the group consisting of breath freshening compounds,flavors used for oral hygiene, fragrances used for oral hygiene, activeagents used for oral cleansing, and active agents used for dentalcleansing.
 3. The composition according to claim 1, wherein thewater-soluble polymer is hydroxypropylmethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol,xanthane gum, tragacantha, guar gum, acacia gum, arabic gum, polyacrylicacid, methylmethacrylate copolymer, carboxyvinyl copolymers, or mixturesthereof.
 4. The composition according to claim 1, wherein theconcentration of the water-soluble polymer in the dry film is between 20and 75%.
 5. The composition according to claim 1, further comprising oneor more plasticizers or surfactants.
 6. The composition according toclaim 5, wherein the surfactant comprises a polyoxyethylene sorbitanfatty acid ester or a α-hydro-ω-hydroxypoly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymer.
 7. The compositionaccording to claim 5, wherein the surfactant comprises a polyoxyethylenealkyl ether or a polyoxyethylene castor oil derivative.
 8. Thecomposition according to claim 1, wherein the polyalcohol is selectedfrom glycerol, polyethylene glycol, propylene glycol, or glycerolmonoesters with fatty acids.
 9. The composition according to claim 1,wherein the pharmaceutically active ingredient is selected from thegroup of hypnotics, sedatives, antiepileptics, awakening agents,psychoneurotropic agents, neuromuscular blocking agents, antispasmodicagents, antihistaminics, antiallergics, cardiotonics, antiarrhythmics,diuretics, hypotensives, vasopressors, antitussive expectorants, thyroidhormones, sexual hormones, antidiabetics, antitumor agents, antibioticsand chemotherapeutics, or narcotics.